奥拉帕尼杂质68

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Pyridine (0.7 cm3) and a solution of 3-bromo-4-fluorobenzyl alcohol (5 g) in dry toluene (50 cm3) were added to a stirred solution of phosphorus tribromide (2.64 g) in dry toluene (50 cm3) under an atmosphere of nitrogen, the temperature of the reaction mixture being maintained at -10° C. during the addition. The mixture was allowed to warm to the ambient temperature (ca. 20° C.) and was stirred for one hour. The mixture was poured into ice and the products extracted into diethyl ether. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulphate to give an orange-red oil, shown by thin layer chromatography to contain two components. NMR spectroscopy of the mixture suggested the presence of a phosphite intermediate and the required product. The oil was redissolved in dry toluene (50 cm3) and further phosphorus tribromide (0.2 g) and pyridine (0.7 cm3) added. The mixture was stirred at 50° C. for 4 hours and then stood at the ambient temperature for 17 hours. The mixture was poured into ice and sodium bicarbonate solution added to neutralise the resulting acid mixture. The products were extracted into diethyl ether, and the combined organic extracts washed with brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent gave a white solid which was purified by flash column chromatography on a silica gel support, eluting with petroleum ether containing 5% by volume diethyl ether, to give the title compound (4.6 g) as a colourless crystalline solid. to warm to the ambient temperature (ca. 20° C.) The mixture was poured into ice the products extracted into diethyl ether The combined organic extracts were washed with brine dried over anhydrous magnesium sulphate to give an orange-red oil

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Lithium aluminium hydride (0.075 g) was added to a stirred solution of 3-bromo-4-fluorobenzaldehyde (1.2 g) in dry tetrahydrofuran (20 cm3), the temperature being maintained below 5° C. by external cooling. The temperature of the reaction mixture was then allowed to rise to the ambient value (ca 20° C.) and the mixture was stirred for 2 hours; GLC analysis of a withdrawn sample indicated 82% conversion at this time, and further lithium aluminium hydride (0.025 g) was therefore added to the mixture. After a further 1.5 hours GLC analysis indicated that the reaction was complete. The mixture aas poured into water (20 cm3) and the products extracted into diethyl ether (3×20 cm3). The combined ethereal extracts were washed with brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave the title compound in high purity. the temperature being maintained below 5° C. by external cooling to rise to the ambient value (ca 20° C.) was therefore added to the mixture After a further 1.5 hours GLC analysis indicated that the reaction the products extracted into diethyl ether (3×20 cm3) The combined ethereal extracts were washed with brine dried over anhydrous magnesium sulphate Evaporation of the solvent under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A misture of 29.4 g (0.3 mol) of sulphuric acid, 50 ml of water and 2 ml of Aliquat 336 (tricapryl-methyl-ammonium chloride) was added to a solution of 20.5 g (0.1 mol) of 3-bromo-4-fluoro-benzyl alcohol in 250 ml of methylene chloride at room temperature. Thereafter, 9.7 g (0.033 mol) of potassium dichromate were added to the reaction mixture and the temperature was kept at about 25° C. for 2 hours by cooling slightly. After adding 100 ml of water, the organic phase was separated off and the aqueous phase was extracted once more with 100 ml of methylene chloride. The organic phases were washed twice with 100 ml of water each time, then once with 100 ml of saturated sodium bicarbonate solution and once more with 100 ml of water, dried over sodium sulphate and evaporated in vacuo. The residue was distilled. 16.3 g (81% of theory) of 3-bromo-4-fluoro-benzaldehyde were obtained in this manner as a colorless oil with a boiling point of 65° C./0.3 mm Hg. by cooling slightly the organic phase was separated off the aqueous phase was extracted once more with 100 ml of methylene chloride The organic phases were washed twice with 100 ml of water each time once with 100 ml of saturated sodium bicarbonate solution and once more with 100 ml of water, dried over sodium sulphate evaporated in vacuo The residue was distilled

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 10.2 g (0.05 mol) of 3-bromo-4-fluoro-benzyl alcohol were added to a mixture of 10 g of nitric acid (density: 1.4) and 5 ml of water at 30°-35° C. and the mixture was then stirred at room temperature for 5 hours. After adding 30 g of ice, sodium hydroxide solution was added to the mixture until the pH value reached 13, and the mixture was then extracted by shaking with 200 ml of toluene. The organic phase was washed three times with 50 ml of water each time, dried over sodium sulphate and then evaporated. The residue was distilled. 6.1 g (60% of theory) of 3-bromo-4-fluoro-benzaldehyde were thus obtained in the form of an oil which slowly solidified and had a melting point of 29°-31° C. was added to the mixture until the pH value the mixture was then extracted by shaking with 200 ml of toluene The organic phase was washed three times with 50 ml of water each time dried over sodium sulphate evaporated The residue was distilled

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 45.9 g (0.225 mol) of 3-bromo-4-fluoro-benzyl alcohol in 45 ml of methylene chloride was added dropwise to a suspension of 78 g of pyridine/CrO3 /HCl in 450 ml of methylene chloride. During this addition, the temperature of the mixture rose to about 40° C. The mixture was then subsequently stirred for 1 hour, the organic phase was decanted from the chromium salts and the solvent was distilled off in vacuo. The residue was distilled. 39 g (86% of theory) of 3-bromo-4-fluoro-benzaldehyde with a boiling point of 63°-65° C./0.3 mm Hg were thus obtained. During this addition rose to about 40° C the organic phase was decanted from the chromium salts the solvent was distilled off in vacuo The residue was distilled

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (3-Bromo-4-fluorophenyl)methanol (0.264 g, 1.29 mmol) was dissolved in DCM (3 mL). The solution was cooled to 0 deg, and tribromoborane (1.0 M in DCM, 0.863 ml, 0.863 mmol) was added. The mixture was stirred at 0 deg for 1 h, then rt for 1 h. The reaction was quenched with water, and the mixture was transferred to a separatory funnel with half-saturated NaHCO3 (15 mL), and the aqueous phase was extracted with DCM (3×20 mL). The organics were combined, washed with half-saturated brine (5 mL), dried over sodium sulfate and concentrated. Purification of the residue through silica gel (40 mL) using 5% EtOAc-hexane afforded the title compound. The solution was cooled to 0 deg rt for 1 h The reaction was quenched with water the mixture was transferred to a separatory funnel with half-saturated NaHCO3 (15 mL) the aqueous phase was extracted with DCM (3×20 mL) washed with half-saturated brine (5 mL) dried over sodium sulfate concentrated Purification of the residue through silica gel (40 mL)